Individualization of dosage Regimen

1. Individualization of dosage Regimen

2. Contents • Introduction to Dosage Regimen. • Approaches to design dosage regimen. • Dose size, Frequency and Accumulation. • Individualization. • Steps Involved in Individualization of Dosage Regimen. • Dosing of Drugs in Neonates, Infants and Children. • Dosing in Geriatrics. • Dose adjustment in Renal and hepatic impairment.

3. Introduction • Dosage Regimen - Dosage regimen is defined as the manner in which the drug is taken. • For some drugs like analgesics single dose is efficient for optimal therapeutic effect however the duration of most illnesses are longer than the therapeutic effect produced by a single dose, In such cases drugs are required to be taken on a repetitive bases over a period of time depending upon the nature of illness. • An optimal multiple dosage regimen is the one in which the drug is administered in suitable doses with sufficient frequency that ensures maintenance of plasma conc. Within the therapeutic window for entire duration of therapy.

4. Approaches to Design of Dosage regimen Various approaches employed in designing of dosage regimen are • Empirical Dosage regimen : Is designed by physicians based on empirical data, Personal experience and Clinical observations. This method is however not very accurate. • Individualization of Dosage regimen : Is the most accurate approach and is based on the pharmacokinetics of drug in the individual patient. The approach is suitable for hospitalized patients but is quite expensive. • Dosage regimen on population Averages : Most often used approach. The method is based on one of the two models – 1. Fixed Model. 2. Adaptive model.

5. Fixed model : Here, Population average pharmacokinetic parameters are used directly to calculate the dosage regimen. Adaptive model : It is based on both population average pharmacokinetic parameters of the drug as well as patient variables such as weight, age, sex, body surface area and known patient pathophysiology such as renal diseases. Irrespective of the route of administration and complexity of pharmacokinetic equations, the two major parameters that can be adjusted in developing a dosage regimen are: • The Dose Size- Quantity of drug administered at one time • The Dose Frequency- The time interval between doses.

6. Dose Size- • The magnitude of both therapeutic and toxic responses depends upon dose size. • Dose size calculation requires the knowledge of amount of drug absorbed after administration of each dose. Greater the dose size greater the fluctuations between Css,max and Css,min during each dosing interval and greater the chances of toxicity.

7. For drugs administered chronically, dose size calculation is based on average steady state blood levels and is computed from the above equation : Xss,av = 1.44FX0t1/2 ז Where X0 = Maintenance dose, F = Fraction of dose absorbed, ז= Dosing interval t1/2= Half life 1.44 = Reciprocal of 0.693

8. Dosing Frequency– • The Dosing Interval (inverse of dosage frequency) is calculated on the basis of half-life of the drug. • If the interval is increased and dose is unchanged, Cmax, Cmin, Cav decreases but the ratio Cmax/Cmin increases. • Opposite is observed when the dosing interval is reduced or dosing frequency is increased. It also results in greater accumulation of drug in the bodyand toxicity.

9. A proper balance should be obtained between dose frequency and size to attain steady state conc. And with minimum fluctuations to ensure therapeutic efficacy and safety. • For drugs with wide therapeutic index such as penicillin's, Larger doses may be administered at longer intervals (more than half life of drug) without any toxicity effects. • For drugs with narrow therapeutic index such as digoxin, small doses with frequent intervals (less than half life of drug) is better to obtain a profile with least fluctuations which is similar to that observed with controlled drug release systems.

10. Drug Accumulation during Multiple Dosing : • Accumulation occurs because drug from previous doses has not been removed completely. • As the amount of drug in the body increases due to accumulation, the rate of elimination also rises proportionally until a steady state or plateau is reached when the rate of drug entry into the body equals the rate of exit. • Thus, the extent to which a drug accumulates in the body during multiple dosing is independent of dose size and is the function of a. Dosing Interval and b. Elimination half-life. The extent to which a drug will accumulate in the body with any dose interval in a patient can be derived from information obtained with a single dose and is given by Accumulation Index Rac.

11. Rac = 1 1-e -KEז

12. Loading and Maintenance Dose : • A drug does not show therapeutic activity unless it reaches the desired steady state. Plateau can be reached immediately by administering a dose that gives the desired steady state instantaneously before commencement of maintenance dose Xo. • Such an Initial dose or first dose intended to be therapeutic is called as loading dose or priming dose Xo,L. Equation for calculating Loading dose is Xo,L= Css,av Vd F • For drugs having low therapeutic indices the loading dose maybe divided into smaller doses to be given at various intervals before the first maintenance dose. When Vd is not known the loading dose can be calculated by the following equation :

13. Xo,L = 1 (1-e –Ka ז )(1-e –KE ז) • When the drug is given I.V. or when absorption is extremely rapid, the absorption phase is neglected and the above equation reduces to accumulation index : Xo,L = 1 = Rac Xo (1-e–KE ז) • The ratio of loading dose to maintenance dose Xo,L/Xo is called as dose ratio. As the rule when ז = t1/2 , dose ratio equals 2.0, ז > t1/2 , dose ratio is smaller than 2.0 ז < t1/2 , dose ratio is grater than 2.0 .

15. Maintenance Dose : A maintenance dose is the maintenance rate [mg/h] of drug administered equal to the rate of elimination at steady state. It is also defined as the amount of drug required to keep a desired mean steady state concentration in the tissues. It is administered after L.D. • Calculation of Maintenance Dose : The required maintenance dose may be calculated as : MD = CpCL F Where, MD – Maintenance dose rate (mg/L) Cp – desired peak Conc. Of drug (mg/l) CL – Clearance of drug in body and F – Bioavailability.

16. Individualization • Rational drug therapy requires Individualization of Dosage regimen to fit a particular patient’s needs. The application of Pharmacokinetic principles in the dosage regimen design for the safe and effective management of illness in individual patient is called as ClinicalPharmacokinetics. • Same dose of drug may produce large differences in pharmacologic response in different individuals, this is called as Intersubjectvariability. • In other words it means that the dose required to produce a certain response varies from individual to individual.

17. Advantages of Individualization : • Individualization of dosage regimen help in development of dosage regimen which is Specific for the patient. • Leads to decrease in Toxicity and side effects and increase in pharmacological drug efficacy. • Leads to decrease in allergic reactions of the patient for the drug if any. • Patient compliance increases etc.

18. Sources of Variability 1. Pharmacokinetic Variability – • Due to difference in drug concentration at the site of action (as reflected from plasma drug concentration) because of individual differences in Drug absorption, Distribution, Metabolism and Excretion. 2. Pharmacodynamics Variability – • Which is attributed to differences in effect produced by a given drug concentration. • The Major cause of variability is Pharmacokinetic variability. Difference in the plasma conc. levels of given in the same individual when given on different occasions is called as “IntersubjectVariability”

19. It is rarely encountered in comparison to Inter-individual variations. The differences in variability differ for different drugs. Some drugs shows greater variability than others • Major causes of Intersubject Pharmacokinetics Variability are – • Genetics. • Diseases. • Age. • Body Weight and • Drug-Drug Interactions. • Less important Causes are : • Pharmaceutical formulations • Route of administration • Environmental factors and Patient non-compliance.

20. The main objective of Individualization is aimed at optimizing the Dosage regimen. An Inadequate therapeutic response calls for a higher dosage whereas drug related toxicity calls for a reduction in dosage. • Thus in Order to aid individualization, A drug must be made available in dosage forms of different strengths. The number of dose strengths in which the drug should be made available depends upon 2 Major Factors - 1. The Therapeutic index of the drug and 2. The degree of Inter-subject Variability. • Smaller the therapeutic index greater the variability, more the number of dose, strengths required.

21. Steps Involved in Individualization of Dosage Regimen Based on the assumption that all patients require the same plasma conc. range for therapeutic effectiveness, the steps involved in the individualization of dosage regimen are : • Estimation of Pharmacokinetic Parameters in individual patients and to evaluate the degree of Variability. • Attributing the Variability to some measurable characteristics such as hepatic or renal diseases, Age, weight etc. • Designing the new dosage regimen from the collected data.

22. The design of new dosage regimen involves – 1. Adjustment of dosage or 2. Adjustment of dosing interval or 3. Adjustment of both dosage and dosing interval. • Dosing of Drugs In Obese Patients: The apparent volume of distribution is greatly affected by changes in body weight since the latter is directly related to vol. of various body fluids. The Ideal Body Weight (IBW) foe men and women can be calculated from following formulae: IBW (Men) = 50 kg+/- 1kg/2.5cm above or below 150cm in height. IBW (Women) = 45kg +/- 1kg/2.5cm above or below 150cm in height.

23. Any Person Whose body Weight Is more than 25% above the IBW is considered Obese. Generalizations regarding drug distribution and dose distribution in obese patients : • For drugs such as Digoxin that do not significantly distribute in excess body space, Vd do not change and hence dose should be calculated on IBW basis. • For polar drugs like antibiotics (Gentamicin) which distribute in excess fat of obese patients to less extent then other tissues the dose should be lower than per kg total body weight basis but more than that on IBW basis.

24. Dosing of Drugs in Neonates, Infants and Children : Neonates, Infants and children require different dosages than that of adults because of differences in the body surface area, TBW and ECF on per kg body weight basis. Dose for such patients are calculated on the basis of their body surface area not on body weight basis. The surface area in such patients are calculated by Mosteller’s equation: SA (in m2) = (Height x Weight)1/2 60 Infants and children require larger mg/kg doses than adults because: • Their body surface area per kg body weight is larger and hence • Larger volume of distribution (particularly TBW and ECF) TBW- Total body water. ECF- Extra cellular fluid.

25. The child's Maintenance dose can be calculated from adult dose by the following by the following equation : Child’s dose = SA of child in m2 x Adult dose 1.73 Where 1.73 is surface area in m2 of an avg. 70kg adult. Since the surface area of a child is in proportion to the body weight according to the following equation, SA(in m2)= Body weight (in kg) The following relationship can also be written for child’s dose: Child’s dose = weight of child in kg x adult dose 70

26. As the TBW in neonates is 30% more than that in adults, • The Vd for most water soluble drugs is larger in infants and • The Vd for most lipid soluble drugs is smaller . Accordingly the dose should be adjusted. • Dosing of drugs in Elderly : • Drug dose should be reduced in elderly patients because of general decline in body function with age. • The lean body mass decreases and body fat increases by almost 100% in elderly persons as compared to adults. • Vd of water soluble drugs may decrease and that of lipid soluble drugs like diazepam increases with age. • Age related changes in renal and hepatic functions greatly alters the clearance of drugs.

27. The equation that allows calculation of maintenance dose in such patients is given as follows : Patients dose = (weight in Kg) (140 - age in years) x adult dose 1660 • Dosing of drugs in Hepatic diseases : • The influence of Hepatic disorder on the drug bioavailability & disposition is unpredictable because of the multiple effects that liver produces. • The altered response to drugs in liver disease could be due to decreased metabolizing capacity of the hepatocytes, impaired biliary elimination, due to biliary obstruction (e.g. Rifampicin accumulation in obstruction jaundice)

28. Impaired Hepatic blood flow leading to an increase in bioavailability caused by a reduction in first pass metabolism (e.g. Bioavailability's of Morphine and Labetalol have been reported to double in patients with Cirrhosis) • Decreased protein binding and increased toxicity of drugs highly bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired albumin production, altered volume of distribution of drugs due to increased extracellular fluid. • Oedema in liver disease may be increased by drugs that cause fluid retention (e.g. Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone). • Generally, drug doses should be reduced in patients with hepatic dysfunction since clearance is reduced & bioavailability is increased in such a situation.

29. Examples of drugs who's drug conc. Changes due to hepatic impairment : • High extraction ratio • Antidepressants • Chlorpromazine/haloperidol • Calcium channel blockers • Morphine • Glyceryl trinitrates • Levodopa • Propranolol

30. Low extraction ratio • Non-steroidal anti-inflammatory drugs • Diazepam • Carbamazepine • Phenytoin • Warfarin Extraction Ratio – is the measure in renal physiology, Primarily used to calculate renal plasma flow in order to evaluate renal function. It is the amount of compound entering the kidney that got excreted into the final urine. Extraction ratio of the drugs ranges from 0 -1.5 l/min. High Extraction Ratio - Less than 0.3 Low Extraction Ratio - More than 0.7

31. Dosing of drugs in Renal Disease • In patient with renal failure, the half life of the drug is increase and its clearance drastically decreases if it is predominantly eliminated by way of excretion. • Hence, dosage adjustment should take into account the renal function of the patient and the fraction of unchanged drug excreted in urine. • There are two additional method for dose adjustment in renal insufficiency if the Vd change is assumed to be negligible. The adjustment of drug dosage in case of renal disease are carried out by mainly three approaches : • Dose adjustment based on Total body clearance. • Dose adjustment based on Elimination rate constant or Half life. • Dose adjustment in renal failure

32. Dose adjustment based on Total body clearance : • The average drug conc. at steady state Css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval ז & clearance Cl T of the drug. Css,av = Fx0/ClTז Css,av = F x 1/ClT x x0/ז To be kept Assumed Decreased Needs Constant Constant due to Disease adjustment

33. If ClT' , X0 ' &' זrepresents the values for the renal failure patient, then the eq. for dose adjustment is given as Css,av = x0/ClT ז = x0 / Cl’T ז‘ • Rearranging in terms of dose & dose interval to be adjusted, the eq. is Xo’ = Cl’T Xo ז‘ ClT ז • From the above eq., the regimen can be adjusted by reduction in dosage or increase in dosing interval or a combination of both.

34. Dose adjustment based on Elimination rate constant or half life : • The average drug conc. at steady-state Css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval ז & volume of distribution vd& t1/2 of the drug. Css,av = 1.44 F X0 t1/2 Vd ז • Where, the coefficient 1.44 is the reciprocal of 0.693.

35. To be kept Assumed Decreased Needs Constant Constant due to Disease adjustment Css,av = 1.44 F X t1/2XX0 Vd ז • If t1/2 ' , X0 ' & ז ' represents the values for the renal failure patient, then the eq. for dose adjustment is given as • Css,av = t1/2 Xo = t1/2 ‘ Xo’ • ז ז'

36. Rearranging in terms of dose & dose interval to be adjusted, the eq. is Xo’ = t1/2 Xo ז ‘ t‘1/2 ז • Because of prolongation of half life of a drug due to reduction in renal function, the time taken to achieve the desired plateau takes longer if the more severe is dysfunction, hence such patient sometimes need loading dose.

38. Antiviral drugs Renal clearance is the major route of elimination for many antivirals. In patients with renal impairment, renal clearance of these drugs is reduced and the elimination half-life is significantly prolonged. As a result, normal doses will accumulate and may lead to neurological signs such as dizziness, confusion, hallucinations, somnolence and convulsions etc. • Hypoglycemic drugs • Metformin Metformin has been associated with rare but potentially fatal lactic acidosis. This is thought to result from accumulation of metformin when renal impairment reduces renal clearance.

39. Insulin Renal elimination accounts for up to half of the clearance of insulin, so as renal failure progresses, less insulin is excreted so smaller doses are required. • Allopurinol Allopurinol is used in the management of gout to lower serum and urinary uric acid concentrations. As allopurinol, and its active principal metabolite oxypurinol, are mainly excreted in the urine, they accumulate in patients with poor renal function so the dose should be reduced.

40. Diseases are the major source of variation in drug response. Both pharmacokinetic and Pharmacodynamics of many drugs are altered by disease other than the one which is being treated. • Disease state : • Renal dysfunction • Uremia • Renal dysfunction : • It greatly impair the elimination of drug especially those that are primarily excreted by the kidney. • Causes of renal failure are hypertension, diabetes mellitus etc.

41. Uremia : • It is characterized by impaired Glomerular filtration and accumulation of fluid and protein metabolism. • In both the cases the half life of the drug are increased as a consequences drug accumulation and toxicity increases.

42. References • Bio pharmaceutics and Pharmacokinetics – A Treatise by D.M Brahmankar and Sunil B. Jaiswal. • Bio pharmaceutics and Pharmacokinetics by P.L Madan JAYPEE Publication. • Internet sources : Google : www.astralianprescriber.com Volume 32 Number 2 April 2009. • Applied Bio pharmaceutics and Pharmacokinetics Vth Edition by Leon Shargel.

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